PMID- 12927372
OWN - NLM
STAT- MEDLINE
DCOM- 20031030
LR  - 20190819
IS  - 0300-483X (Print)
IS  - 0300-483X (Linking)
VI  - 190
IP  - 3
DP  - 2003 Aug 28
TI  - Liver inflammation during monocrotaline hepatotoxicity.
PG  - 155-69
AB  - Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that causes 
      hepatotoxicity in humans and animals. Human exposure occurs from consumption of 
      contaminated grains and herbal teas and medicines. Intraperitoneal injection 
      (i.p.) of 300 mg/kg MCT in rats produced time-dependent hepatic parenchymal cell 
      (HPC) injury beginning at 12 h. At this time, an inflammatory infiltrate 
      consisting of neutrophils (PMNs) appeared in areas of hepatocellular injury, and 
      activation of the coagulation system occurred. PMN accumulation was preceded by 
      up-regulation of the PMN chemokines cytokine-induced neutrophil chemoattractant-1 
      (CINC-1) and macrophage inflammatory protein-2 (MIP-2) in the liver. The monocyte 
      chemokine, monocyte chemoattractant protein-1 (MCP-1), was also upregulated. 
      Inhibition of Kupffer cell function with gadolinium chloride (GdCl(3)) 
      significantly reduced CINC-1 protein in plasma after MCT treatment but had no 
      effect on hepatic PMN accumulation. Since inflammation can contribute to either 
      pathogenesis or resolution of tissue injury, we explored inflammatory factors as 
      a contributor to MCT hepatotoxicity. To test the hypothesis that PMNs contribute 
      to MCT-induced HPC injury, rats were depleted of PMNs with a rabbit anti-PMN 
      serum prior to MCT treatment. Anti-PMN treatment reduced hepatic PMN accumulation 
      by 80% but had no effect on MCT-induced HPC injury or activation of the 
      coagulation system. To test the hypothesis that Kupffer cells and/or tumor 
      necrosis factor-alpha (TNF-alpha) are required for MCT-induced HPC injury, rats 
      were treated with either GdCl(3) to inhibit Kupffer cell function or 
      pentoxifylline (PTX) to prevent synthesis of TNF-alpha. Neither treatment 
      prevented MCT-induced HPC injury. Results from these studies suggest that PMNs, 
      Kupffer cells and TNF-alpha are not critical mediators of MCT hepatotoxicity. 
      Accordingly, although inflammation occurs in the liver after MCT treatment, it is 
      not required for HPC injury and possibly occurs secondary to hepatocellular 
      injury.
FAU - Copple, Bryan L
AU  - Copple BL
AD  - Institute for Environmental Toxicology, B-346 Life Sciences Building, Michigan 
      State University, East Lansing, MI 48824, USA.
FAU - Ganey, Patricia E
AU  - Ganey PE
FAU - Roth, Robert A
AU  - Roth RA
LA  - eng
GR  - ES 04139/ES/NIEHS NIH HHS/United States
GR  - ES 05866/ES/NIEHS NIH HHS/United States
GR  - T32 ES 07255/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (CXCL1 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL1)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Chemokines)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Chemotactic Factors)
RN  - 0 (Cxcl1 protein, rat)
RN  - 0 (Cxcl2 protein, rat)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Monokines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 73077K8HYV (Monocrotaline)
RN  - 9005-49-6 (Heparin)
RN  - AU0V1LM3JT (Gadolinium)
RN  - P7082WY76D (gadolinium chloride)
RN  - SD6QCT3TSU (Pentoxifylline)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Chemical and Drug Induced Liver Injury/*etiology/immunology/metabolism/pathology
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Chemokine CXCL1
MH  - Chemokine CXCL2
MH  - Chemokines/biosynthesis/blood/genetics
MH  - *Chemokines, CXC
MH  - Chemotactic Factors/biosynthesis/blood/genetics
MH  - Enzyme Inhibitors/pharmacology
MH  - Gadolinium/pharmacology
MH  - Heparin/pharmacology
MH  - Immunohistochemistry
MH  - Intercellular Signaling Peptides and Proteins/biosynthesis/blood/genetics
MH  - Kupffer Cells/drug effects/metabolism
MH  - Male
MH  - Monocrotaline/*toxicity
MH  - Monokines/biosynthesis/genetics
MH  - Neutrophils/drug effects/immunology/metabolism
MH  - Pentoxifylline/pharmacology
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/metabolism
MH  - Up-Regulation
EDAT- 2003/08/21 05:00
MHDA- 2003/10/31 05:00
CRDT- 2003/08/21 05:00
PHST- 2003/08/21 05:00 [pubmed]
PHST- 2003/10/31 05:00 [medline]
PHST- 2003/08/21 05:00 [entrez]
AID - S0300483X03001641 [pii]
AID - 10.1016/s0300-483x(03)00164-1 [doi]
PST - ppublish
SO  - Toxicology. 2003 Aug 28;190(3):155-69. doi: 10.1016/s0300-483x(03)00164-1.